Intrathecal Clonidine as Spinal Anaesthesia Adjuvant—Is there a Magical Dose?

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Chapter 5
Intrathecal Clonidine as Spinal Anaesthesia Adjuvant —
Is there a Magical Dose?
Víctor M. Whizar-Lugo, Juan C. Flores-Carrillo and
Susana Preciado-Ramírez
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/58712
1. Introduction
Clonidine was synthesized in 1962 as nasal decongestant, and marketed as antihypertensive
in 1972. Bloor and Flacke in 1982 [1] demonstrated in mongrel dogs that intravenous clonidine
5 and 20 µg/kg decreased halothane MAC by 42% and 48% respectively. Since then, clonidine
has been used by anaesthesiologists as an anaesthetic adjunct to provide increased perioper‐
ative cardiovascular and sympathoadrenal stability, to enhance general and regional anaes‐
thesia, as well as sedation and analgesia. [2, 3] In 1999, dexmedetomidine, a novel selective
and specific alpha2 agonist, was approved for postoperative sedation in intensive care patients,
and has also been investigated in general anaesthesia, regional anaesthesia and pain treatment.
Basic research in animals and clinical studies in humans performed with epidural clonidine
have shown its analgesic effects, with less side effects than any other neuroaxial anaesthesia
adjuvant. Similar results were also obtained with intrathecal injection of clonidine. Due to the
short duration of analgesic action by the latter route, the extradural administration is the most
studied. Epidural administration of clonidine has been widely utilized; indeed, the FDA has
only approved peridural use of clonidine infusion in chronic pain patients. There are many
publications with epidural clonidine for intraoperative surgical pain as an adjunct to general
anaesthesia and epidural anaesthesia, postoperative pain, pediatrics, and labour analgesia. It
has been used alone, or in combination with local anaesthetics, opioids, in bolus, or by
continuous infusion.
Intrathecal administration of clonidine is an interesting alternative route of administration. As
an alpha2 agonist, spinal injected clonidine prolongs sensory and motor block, increases
sedation and may potentiate hypotension and bradycardia. It has been used in high (> 150 µg),
low (< 150 µg) and small (< 75 µg) doses. High doses 150, 300 and 450 µg produce dose
© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons
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distribution, and reproduction in any medium, provided the original work is properly cited.
98 Topics in Spinal Anaesthesia
dependent analgesia, enhance spinal anaesthesia, with relative hemodynamic stability.
Furthermore, doses of 15 and 30 µg in addition to spinal local anaesthetics provide better
sensory and motor block compared to local anaesthetics alone. [4, 5]
The optimal dose of spinal clonidine remains unknown. For short ambulatory procedures 15
to 75 µg added to local anaesthetics enhance spinal anaesthesia without negative impact on
home discharge criteria. For short-stay or longer hospitalization surgeries, doses from 150 up
to 450 µg of clonidine as adjuvant for any local anaesthetics are safe, prolongs motor and
sensory block, and reduces the need of postoperative opioids.
This chapter updates current data on dose-response relationship of subarachnoid clonidine
when added as adjunct to spinal local anaesthetics and/or spinal opioids in different clinical
surgery scenarios, as well as for postoperative analgesia and labour pain.
2. Spinal additives
Spinal adjuvant drugs have been used since the beginning of subarachnoid anaesthesia.
Adrenaline, an alpha2 agonist, was the first drug used to enhance duration of spinal anaes‐
thesia, and morphine was the first opioid injected with eucaine in the lumbar spinal space to
relieve vertebral pain. [6] After the first article on spinal analgesia using opioids written by
Yaksh and Rudy in 1976, [7] the neuroaxial route to inject opioids as adjuvants drugs grew
logarithmically. Morphine, fentanyl, sufentanyl and many more agonist opioids have proven
their safety and efficacy to decrease the dose of local anaesthetics, to facilitate a faster recovery,
and effective postoperative analgesia. There are many receptors which modulates spinal pain
response; however, there are only few FDA approved drugs to be used via subarachnoid as
adjuvants or sole medications.
Many drugs have being injected into the spinal or peridural space in order to provide analgesia
and/or to enhance neuraxial anaesthesia. Nowadays, opioids are the more frequently used
spinal additives, but their side effects may limit its use; pruritus, urinary retention and late
respiratory depression. There are studies with intrathecal adjuvants that have not been
approved to be used in spinal anaesthesia: midazolam, ketamine, neostigmine, magnesium
sulphate, calcium channel blockers, nonsteroidal anti-inflammatory, dexmedetomidine,
tizanidine, etcetera.
3. Alpha2 adrenergic agonist drugs
Alpha2 agonist medications are used as adjuvants in anaesthesia and analgesia. They can be
prescribed orally, transdermally, intravenously, perineuraly, or through the neuroaxial route.
Beside analgesia and sedation, they decrease sympathetic tone and attenuate the stress
response to anaesthesia and surgery. Although adrenaline was the first alpha2 agonist used
intrathecally, it is no longer recommended. Nowadays, clonidine is the most used alpha2
Intrathecal Clonidine as Spinal Anaesthesia Adjuvant — Is there a Magical Dose? 99
http://dx.doi.org/10.5772/58712
agonist in neuroaxial anaesthesia, even though dexmedetomidine has also recently been
studied for epidural and spinal anaesthesia adjuvant. Clonidine acts as a selective partial
agonist with a ratio of 200:1, whereas dexmedetomidine is highly selective with a ratio of
1600:1. Tizanidine, 5-bromo-N-[4, 5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK-14,
304], and moxonidine are other alpha2 agonists with a potential neuroaxial use. [8, 9, 10, 11]
More than 90 patents have been deposited recently regarding different methods of alpha2
modulation (use of agonists or antagonists, nucleic acids and polypeptides) for diagnosis,
prognosis and treatment of disorders involving this receptors.
4. Clonidine
This prototypical alpha2 adrenergic receptor agonist was developed in the early 1960s. It is an
imidazoline derivative that exists as a mesomeric compound. It has a molecular weight of
266.56, chemical name is Benzenamine, 2, 6-dichloro-N-2-imidazolindinylidene monohydro‐
chloride and 2-[[2, 6-dichlorophenyl) imino] imidazolidine monohidrochloride. Figure 1
shows its structural formula (C9H9Cl2N3 HCl). Clonidine stimulates alpha2 adrenoreceptors
in the brain and spinal cord, resulting in reduction of sympathetic outflow from the central
nervous system and in decreased in peripheral resistance, renal vascular resistance, plasma
renin activity, heart rate, cardiac output, and blood pressure. Normal postural reflexes are
intact; therefore, orthostatic symptoms are mild and infrequent. Plasmatic level of clonidine
peaks in approximately 3 to 5 hours and the plasma half-life ranges from 12 to 16 hours. The
half-life increases up to 41 hours in patients with severe renal impairment. Following oral
administration, approximately 75% is bioavailable in men, about 40-60% of the absorbed dose
recovered unchanged in the urine in 24 hours. About 50% of the absorbed dose is metabolized
in the liver. Severe adverse side effects are infrequent, and well tolerated in most patients.
Sedation and dry mouth are the most common side effects, and are usually related to dose and
length of administration. [12, 13]
Figure 1. Structural formula of clonidine
100 Topics in Spinal Anaesthesia
5. Mechanisms of action of spinal clonidine
It has been shown that epidural and spinal administration of clonidine in surgical patients
enhances quality and duration of neuroaxial anaesthesia, reduces dose of local anaesthetics as
well as others neuroaxial additives such opioids. It also produces a short period of postoper‐
ative analgesia, and lowers the dose of systemic postoperative analgesics.
G-protein-coupled receptors (GPCRs) are the largest and most diverse superfamily of mem‐
brane receptors responsible for signaling between cells and tissues, mediating most cellular
responses to hormones and neurotransmitters, playing important physiological roles in
homeostasis. They are a major drug targets. The alpha2 adrenoceptors are membrane proteins
belonging to these superfamily GPCRs, that form a group of 3 to 4 gene polymorphic products,
that mediate major central nervous system actions of norepinephrine and epinephrine,
including control of mood state, arousal, endocrine function, autonomic and somatic motor
outflows, and modulation sensory inputs, including pain. The alpha2 adrenoceptors are
located presynaptically and regulates the release of the neurotransmitter; they are also present
in postsynaptical locations.
Three distinct subtypes have been described, characterized and cloned; alpha2A, alpha2B, and
alpha2C. [14, 15, 16, 17] There is a fourth receptor called alfa2D that has been described and
their functions are still not known, although it appears that this receptor alfa2D is in fact, an
alpha2A-D subtype; the alpha2A in humans and the alpha2D in rats. [18]
Figure 2. Alpha2 adrenoceptors are membrane proteins belonging to the super family GPCRs. There are four sub‐
types. Their stimulation has wide therapeutic effects.
Intrathecal Clonidine as Spinal Anaesthesia Adjuvant — Is there a Magical Dose? 101
http://dx.doi.org/10.5772/58712
The anatomic site of action of the alpha2 agonists involves specific receptors of the spinal dorsal
horn and supraspinaly in the nucleus coereleus in the pons. [19, 20, 21, 22] While the mecha‐
nism and location of action of the sedative effect of these compounds are due to the hyperpo‐
larization of excitable neurons localized in the nucleous coereleus, the analgesic effect of these
drugs is not completely understood, and have a complex mechanism. Alpha 2 agonists induce
analgesia by acting in different places; brain, brain stem, spinal cord and peripheral nerves.
Their supraspinaly analgesic mechanism in the locus coereleus is probably by transduction,
while in the spinal cord is likely related to activation of the descending medullospinal
noradrenergic pathways or to the reduction of spinal sympathetic outflow at presynaptic
ganglionic sites. Clonidine suppresses the generation of action potentials in tonic-firing spinal
dorsal horn neurons. This may be explained, in part, by an interaction with voltage-gated Na
+and K+currents.
Clonidine also acts synergistically with local anaesthetics because of its action of opening
potassium channels.
6. Spinal interactions between alfa2 agonists and opioids
It is an uncommon clinical practice to combine alpha2 agonists and opioids in spinal anaes‐
thesia to either enhance local anaesthetic effects or to provide postoperative analgesia. This
technique is based on the spinal synergism between these two drugs. When morphine and
clonidine are co-administered intrathecally, the resulting antinociception is greater than
expected if the drug responses were additive; thus, a synergistic interaction is present. [23,
24] For the most part, the underlying molecular synergy mechanisms are not known, although
some studies have identified both the delta and the mu-opioid receptors as candidate receptors
capable of interacting synergistically with alpha 2A agonists. Roerig et al [25] found in rats
that interactions between opioid and adrenergic agonists in mouse spinal cord were mediated
by delta and alpha2 receptor subtypes, the synergistic interaction between morphine and
alpha2 adrenergic agonists may involve action at delta opioid receptors, and antagonist action
on these drug interactions is intrincated. Stone and coworkers, [26] in a genetically modified
mouse line expressing a point mutation (D79N) in the alpha2A adrenergic receptor investi‐
gated the role of the alpha2A receptor in alpha2 agonist-evoked analgesia and adrenergic-
opioid synergy. They were able to demonstrate that the alpha2A subtype receptor is the
primary mediator of alpha2 adrenergic spinal analgesia and is necessary for analgesic synergy
with opioids, and concluded that combination therapies targeting the alpha2A receptor and
opioid receptors may be useful in maximizing the analgesic efficacy of opioids while decreas‐
ing total dose requirements. Although others have found that the alpha2C adrenergic receptor
subtype contributes to this synergy, [27] Chabot-Doré and coworkers [28] confirmed that
although other opioid receptors can interact synergistically with alpha2 receptors agonists,
Delta opioid receptor is sufficient for spinal opioid-adrenergic interactions. Protein kinase is
needed for this analgesic synergy. [29]
102 Topics in Spinal Anaesthesia
Analgesic synergy between opioid and alpha2 adrenergic agonists is potentially beneficial by
increasing efficacy and/or reducing the total drug required to produce sufficient pain relief,
and undesired side effects can be minimized.
7. Safety of spinal clonidine
Neurotoxicity has not been reported following the use of intrathecal clonidine and generally
the drug is considered to be safe in this regard. Although subarachnoid administration of
clonidine has not been approved by the FDA or any other regulatory agency in the world, there
are experimental studies that have demonstrated its safety and efficacy when used by this
route. Continuous administration of spinal clonidine in Wistar rats during 14 days failed to
demonstrate neurotoxic damage. [30] Erddivanli and coworkers injected male Sprague-
Dawley rats [31] with 3 µg and 10 µg of intrathecal dexmedetomidine added to bupivacaine;
they found no apparent pathohistological changes 24 hours after a single injection. In male
Kunming mice 1 to 3 µg of dexmedetomidine displayed a robust analgesia via a alpha2-
receptor in a dose dependent manner and no significant pathological impacts on the spinal
cord were noticed, with a potential protective effects of lidocaine induced neural cell damage.
[32] In postnatal rats spinal clonidine produces age and dose-dependent analgesia, without
signs of spinal cord toxicity, even at doses bigger than required for analgesia. [33]
8. Clinical use of spinal clonidine
To enhance spinal anaesthesia and postoperative pain control clonidine can be injected in the
subarachnoid space as an adjuvant drug to opioids or local anaesthetics. A systematic review
by Elia et al [34] including 1, 445 patients using a wide variety of spinal clonidine doses as
adjuvant to subarachnoid bupivacaine, mepivacaine, prilocaine, or tetracaine found that 15 to
150 µg prolonged in a linear, dose-dependent manner, the time to 2 segment regression (range
of means, 14 to 75 minutes) and also delayed the regression time to L2 dermatome (range of
means, 11 to 128 minutes). The time to first analgesic request (median 101 minutes, range 35
to 310] and motor block (median 47 minutes, range 6 to 131] was extended with no relation to
dose. There were fewer episodes of intraoperative pain with clonidine (relative risk, 0.24; 95%
confidence interval [CI], 0.09-0.64; number needed to treat, 13] but more episodes of arterial
hypotension (relative risk, 1.81; 95% CI 1.44-2.28; number needed to harm, 8] without evidence
of dose-responsiveness. The risk of bradycardia was unchanged.
Side effects of intrathecal clonidine include sedation, hypotension and a reduction of the heart
rate. Especially in post-surgical patients these circumstance warrants specific attention.
The following paragraphs discuss spinal clonidine use in different anaesthetic and surgical
scenarios, as well as in the management of postoperative and labour pain.
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9. Ambulatory settings
Spinal anaesthesia side effects are a major concern in some patients and physicians and may
be reluctant to use this technique in ambulatory surgery. [35] Nowadays there are many articles
showing that spinal anaesthesia is a safe and effective technique in this clinical scenario. There
is an special interest to use adjuncts drugs such clonidine in order to decrease local anaesthetic
dose to promptly achieve a recovery profile. [36]
Several investigations in patients undergoing knee arthroscopy have shown that low doses of
clonidine [15 up to 45 µg) added to low doses of intrathecal hyperbaric bupivacaine [5-6 mg)
improves the quality of anaesthesia, prolong the motor block, without affecting time to home
discharge in outpatients. [37] In 60 ambulatory patients undergoing knee arthroscopy Marri‐
virta et al [38] added 75 µg clonidine to 6 mg spinal hyperbaric bupivacaine vs. 6 mg bupiva‐
caine alone. These researchers found that motor block was prolonged in those patients who
received clonidine without affecting home-readiness. Also these patients needed more
vasopressors and had less postoperative pain. Adding clonidine 15 µg to 8 mg of isobaric spinal
ropivacaine [39] did not prolonged motor or sensory blockade, but enhanced anaesthesia
quality for knee arthroscopy. Bigger doses such 75 µg produced significantly longer sensory
and motor blockade [195 ± 40 min and 164 ± 38 min; p < 0.05], but associated with sedation and
hypotension.
In our practice we have good results with doses of 45-150 µg. These doses of spinal clonidine
favor the reduction of local anaesthetics doses and do not prolong the recovery time of our
outpatients.
10. General surgery and urologic procedures
Numerous surgical procedures of the abdominal wall, abdominopelvic cavity, and retroperi‐
toneum can be performed under single injection of local anaesthetics in the spinal space. For
prolonged cases the use of adjuvant drugs improves the quality and increases the duration of
the subarachnoid block. Clonidine has been used successfully in various surgical procedures
of the abdomen and pelvis. Intrathecal clonidine 15, 30, 45 and 75 µg alone, or added to opioids
expand spinal anaesthesia sensory block and duration of motor block, and also provided
prolonged postoperative analgesia. In a randomized study [40] of 73 patients ASA physical
status I and II undergoing gynecological abdominal surgery with spinal bupivacaine 15 mg,
the authors compared clonidine 30 µg, sufentanyl 10 µg, clonidine 15µg plus sufentanil 15 µg
versus a control group. Sensory block to pinprick at 10 min was higher for clonidine and
sufentanil/clonidine groups compared to the control group (p < 0.02]. Anaesthetic time
(Bromage score 2] was also longer for clonidine and sufentanil/clonidine groups compared to
the control and sufentanil groups (p < 0.05]. Time to first rescue analgesics was shorter in the
control group compared to the other groups (p < 0.02]. The dose of intramuscular diclofenac
in 24 hours was higher in the control group compared to all other groups (p < 0.05]. The
incidence of adverse effects and ephedrine consumption were similar among groups. Cloni‐
104 Topics in Spinal Anaesthesia
dine 75 µg associated with 17.5 mg hyperbaric bupivacaine 0.5% for lower abdominal surgeries
[41] with high level spinal anaesthesia (T4] induced a higher incidence of arterial hypotension
but prolongs sensory block and postoperative analgesia similar to clonidine 45 µg. In lower
abdomen surgeries, Yoganarasimha and coworkers [42] compared intrathecal clonidine 75 µg
versus intrathecal neostigmine 50 µg as adjuvant drugs for spinal anaesthesia 0.5% hyperbaric
bupivacaine 12.5 mg; analgesia was prolonged significantly with clonidine [362 ± 36 min)
compared with neostigmine [300 ± 25 min)(p < 0.05]. No serious adverse effects were noted
perioperatively in either group. In an interesting clinical study with 60 patients undergoing
right colon resection under general anaesthesia, preoperative intrathecal clonidine was
superior to bupivacaine to prevent postoperative secondary hyperalgesia; [43] the authors
compared the effect of clonidine 300 µg versus bupivacaine 10 mg intrathecally versus saline
(control group): morphine needs patient controlled postoperative analgesia were less in the
clonidine group [31.5±12 versus 91±25.5 and 43±15 mg, respectively, in groups clonidine,
saline, and bupivacaine: p < 0.05 at 72 postoperative hours). The area of mechanical hyperal‐
gesia at 72 h was 3±5 cm2 in the clonidine group versus 90±30 and 35±20 cm2 in the saline and
bupivacaine groups (p < 0.05]. After 6 months, fewer patients in the clonidine group experi‐
enced residual pain than in the saline group [0 of 20 versus 6 of 20, p < 0.05]. In laparoscopic
procedures done under bupivacaine spinal anaesthesia, clonidine 30 µg produced good
sedation, intra and postoperative analgesia, and abolished shoulder tip pain during the
procedures. [44] For inguinal hernioplasthy [45, 46] adding clonidine 15 or 30 µg to small doses
of hyperbaric bupivacaine enhance spinal anaesthesia, prolongs the time to first analgesic
request, and decreases postoperative pain, compared with bupivacaine alone. Thirty µg
clonidine was associated with higher incidence and duration of hypotension than 15 µg of
clonidine.
Some research has shown the usefulness of intrathecal clonidine in urology procedures,
although there are some controversies. In a controlled, prospective, double-blind investigation
with patients undergoing elective transurethral resection of bladder tumours under spinal
anaesthesia [47] the authors found that adding clonidine 75 µg to prilocaine 75 mg increased
the duration of sensory and motor block and reduced the need for additional postoperative
analgesics by providing excellent analgesia for about 8 hours during recovery period. In a
similar study, 25 µg spinal clonidine improved bupivacaine spinal anaesthesia: shorter time
to achieve complete motor block and sensory block at T9 level, with longer postoperative
analgesia. [48] In 60 patients undergoing transurethral resection of prostate or bladder tumors
Kanazi et al [49] compared clonidine 30 µg, versus dexmedetomidine 3 µg added to 12 mg
spinal hyperbaric bupivacaine, versus bupivacaine alone. Patients treated with alpha2 agonists
had a significantly shorter onset time of motor block and significantly longer sensory and
motor regression times than patients who only received local anaesthetic. The mean time of
sensory regression to the S1 segment was 303 ±75 min for those injected with dexmedetomi‐
dine, 272 ±38 min in the group who received clonidine and 190±48 min in patients with
bupivacaine alone (bupivacaine versus dexmedetomidine and bupivacaine versus clonidine,
p< 0.001]. The regression of motor block to Bromage 0 was 250 ±76 min, 216±35 min, and 163±47
min respectively (bupivacaine versus dexmedetomidine and bupivacaine versus clonidine, p<
0.001]. The onset and regression times were not significantly different between patients treated
Intrathecal Clonidine as Spinal Anaesthesia Adjuvant — Is there a Magical Dose? 105
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with the alpha2 agonists. The mean arterial pressure, heart rate and level of sedation were
similar in the three groups intra-operatively and post-operatively. Andrieu and his group [50]
compared intrathecal morphine 4µg/kg without or with clonidine 4µg/kg, or PCA in patients
undergoing radical retropubic prostatectomy under general anaesthesia with sevorane-N2O.
Adding clonidine to spinal morphine reduced intraoperative use of sufentanil, prolonged time
until first request for PCA rescue, and added prolonged analgesia at rest and during coughing.
In contrast with previous mentioned studies, Larsen et al [51] compared 75 µg versus 150 µg
of clonidine added to 80 mg mepivacaine 4%, versus spinal mepivacaine alone in patients who
had transurethral surgery and found that clonidine had no effect on the onset time, spread or
intensity of subarachnoid anaesthesia. The higher dose prolonged the duration of sensory
block by 50 minutes and the duration of motor block by 40 minutes, while 75 µg had no
significant effect. Heart rate and mean arterial pressure were significantly reduced in both
clonidine groups when compared to plain mepivacaine. There was no significant reduction in
postoperative analgesic demand. They do not recommend the routine addition of clonidine
for spinal anaesthesia with local anaesthetics. There is a reported case of late respiratory
depression (16 h after spinal block) in a 70 year old man undergoing prostatic adenomectomy
done under spinal anaesthesia with 10 mg bupivacaine, 30 µg clonidine and 100 µg morphine.
Intrathecal mixture of morphine-clonidine in older patients must be careful monitored. [52]
10.1. Orthopaedic
Postoperative pain following orthopaedic surgeries has been shown to be a significant negative
factor that delay patient recovery and contributes to serious complications. It may also result
in larger use of healthcare resources and ultimately lead to poor outcomes. The utilization of
multimodal pain management following large orthopaedic surgeries like total joint arthro‐
plasty, total knee replacement, or spinal surgery has positively affected the quality of postop‐
erative care, reduced surgical pain, and decreased the magnitude of opioid consumption and
subsequent dose-related complications. Multimodal spinal anaesthesia-analgesia including
spinal clonidine is safe and may reduce hospital stay, decrease postoperative complications,
and increase patient satisfaction.
In a dose-response prospective study, Strebel et al [53] compared three doses of clonidine (37.5,
75 and 150 µg) added to spinal 0.5% bupivacaine 18 mg in 80 orthopaedics patients. Duration
of sensory block (regression below level L1) was increased in patients receiving intrathecal
clonidine: 311±101 min in 37.5 µg (+8%), 325 ±69 min in 75 µg (+13%), and 337±78 min in those
patients who received 150 µg (+17%) (estimated parameter for dose 0.23 [95% confidence
interval-0.05-0.50]). versus control group 288 ±62 min. Time to first analgesic request was also
prolonged: 343 ±75 min (+16%), 381±117 min (+29%), and 445±136 min (+51%) (estimated
parameter for dose 1.02 [95% confidence interval 0.59-1.45]), respectively compared to control
group 295±80 min. Hemodynamic stability was maintained and they found no differences in
sedation level. van Tuijl and coworkers [37] investigated the effect of 0, 15 and 30 µg of
clonidine added to 5 mg hyperbaric bupivacaine on the duration of motor block, analgesia and
ability to void after knee arthroscopy. They found that clonidine increased motor block
duration by 25 and 34 min respectively. They also found better analgesic quality, and the mean